H-2 associated natural resistance, which includes the phenomenon of hybrid resistance, is one of the most perplexing and difficult problems in immunology. Immunocompromised mice are able to recognize and resist H-2 homozygous hemopoietic cells or tumor cells on the basis of H-2 nonidentity; this nonadaptive resistance can be expressed by H-2 heteozygous F1 mich against parental strain cells. In contrast, H-2 heteozygous cells are not resisted by parental strain mice in spite of the presence of H-2 alloantigens. The hypothesis which forms the basis for this application is that the immunogenetic specificity of H-2 associated natural resistance is not due to classical immune mediators but involves recognition of H-2 linked self markers. Analysis of resistance is hampered by the lack of a convenient and reproducible in vitro assay that has the same immunogenetic specificity as the in vivo phenomenon. In vivo studies ar complicated by the existence of adaptive immune mediators such as natural antibody and T-cells. Mice that are homozygous for the sevre combined immunodeficiency mutation (scid) have an impairment in their ability to successfully rearrange Ig and T-cell receptor genes, but can recognize and resist H-2 nonidentical cells. The immunogenetic specificity, strength and characteristics of resistance in scid mice will be compared with normal mice by monitoring reconstitution of the immune system following bone marrow transplantation and by following the elimination of radiolabeled cells. Scid mice also will be used as a source of cells and serum in developing, through a combination of cellular and molecular approaches, and in vitro assay which mimics the immunogenetic specificity of natural resistance. These studies will test whether the specificity reflects recognition of H-2 directly by NK cells or whether intermediate cell interactions are involved. Classical genetic approaches have been unable to resolve whether the "target antigens" for H-2 associated natural resistance are products of known H-2 loci or of linked Hh genes. Transfection of H-2 homozygous leukemia cell lines with cloned H-2 genes will be used to determine if the transfected cells become refractory to resistance by the gene donor strain, as predicted by the self-recognition hypothesis, and to the determine the antigens involved. The role of differential H-2 haplotype expression in susceptibility to resistance of H-2 heteozygous leukemia cell lines will also be assessed. H-2 associated natural resistance may serve as a first line of defense against neoplastic cells, and these studies might also reveal physiological functions of the MHC outside the realm of classical immunology.